A variety of diseases including asthma, cancers, heart diseases, aneurysms, autoimmune diseases, and viral infections manifest varying symptoms and signs and yet it has been suggested that an abnormal expression (an overexpression or underexpression) of one or a few proteins is a major etiologic factor in many cases. In general, the expression of those proteins is controlled by a variety of transcriptional regulatory factors such as transcription activating factors and transcription suppressing genes.
A representative transcriptional factor NF-κB is a transcriptional regulatory factor consisting of heterodimers p65 and p50. NF-κB is typically localized in the cytoplasm where NF-κB is bound by its inhibitory factor IκB so that intranuclear movement of NF-κB is prevented. However, when a stimulus, such as cytokine, ischemia, reperfusion, or the like, is applied due to any cause, IκB is degraded after phosphorylation. As a result, NF-κB is activated and transferred into the nucleus. In the nucleus, NF-κB binds to an NF-κB binding site on a chromosome and promotes the transcription of a gene downstream thereof. As genes located downstream of the NF-κB binding site, for example, inflammatory cytokines (e.g., IL-1, IL-6, IL-8, tumor necrosis factor α (TNF α), etc.) and adhesion molecules (e.g., VCAM-1, ICAM-1, etc.) are known.
NF-κB may be involved in the onset of progression of tumor malignancy (Rayet B et al., Oncogene 1999 Nov. 22; 18(49)6938-47); NF-κB is involved in response of tumor cells to hypoxia stress (Royds J A et al., Mol Pathol 1998 April; 51(2):55-61); NF-κB inhibits expression of cytokines and adhesion molecules in synovial membrane cells derived from chronic rheumatoid arthritis patients (Tomita T et al., Rheumatology (Oxford) 2000 July; 39(7):749-57); suppression of coordination between a plurality of transcriptional factors including NF-κB changes the malignant phenotypes of various tumors (Denhardt D. T., Crit. Rev. Oncog., 1996; 7(3-4):261-91); downregulation of NF-κB activity due to green tea polyphenol blocks induction of nitric oxide synthesizing enzyme, and suppresses A431 human epidermoid carcinoma cells (Lin J. K., et al., Biochem. Pharmacol., 1999, Sep. 15; 58(6):911-5); amyloid β peptide observed in the brains of Alzheimer's disease patients binds to 75-kD neurotrophic receptor (p75NTR) in neuroblastoma cells to activate NF-κB in a time-dependent manner and a dose-dependent manner (Kuper P, et al., J. Neurosci. Res., 1998, Dec. 15; 54(6):798-804); TNF-α, which is activated by NF-κB, plays an important role in the onset of glomerulonephritis (Ardaillou et al., Bull. Acad. Natl. Med., 1995, January; 179(1)103-15).
NF-κB decoy in vivo blocks expression of cytokines and adhesion molecules in mouse nephritis induced by TNF a (Tomlta N., et al., Gene Ther., 2000, August; 7(15)1326-32); and the like.
It has been suggested that NF-κB suppresses MMP1 and MMP9 which are members of matrix metalloproteinase (MMP) at a transcriptional level (Amplification of IL-1 beta-induced matrix metalloproteinase-9 expression by superoxide in rat glomerular mesangial cells is mediated by increased activities of NF-kappaB and activating protein-1 and involves activation of the mitogen-activated protein kinase pathways. Eberhardt W, Huwiler A, Beck K F, Walpen S, Pfeilschifter J. J Immunol 2000 Nov. 15, 165(10), 5788-97; Nuclear factor kappaB activity is essential for matrix metalloproteinase-1 and -3 upregulation in rabbit dermal fibroblasts. Biochem Biophys Res Commun. Bond M, Baker A H, Newby A C. 1999 Oct. 22, 264(2), 561-7; Synergistic upregulation of metalloproteinase-9 by growth factors and inflammatory cytokines: an absolute requirement for transcription factor NF-kappa B. Bond M, Fabunmi R P, Baker A H, Newby A C. FEBS Lett 1998 Sep. 11, 435(1), 29-34; and Lipopolysaccharide activates matrix metalloproteinase-2 in endothelial cells through an NF-kappaB-dependent pathway. Kim H, Koh G. Biochem Biophys Res Commun. 2000 Mar. 16, 269(2), 401-5).
It is known that in atopic dermatitis pathology or atopic dermatitis model animal, the increase in NF-κB activity induces increase in expression of various cytokines which accompanies infiltration or activation of lymphocytes and thus plays an important role in the onset or progression of the pathology (Role of B7-CD28/CTLA-4 costimulation and NF-kappa B in allergen-induced T cell chemotaxis by IL-16 and RANTES. Hidi R, Riches V, Al-Ali M, Cruikshank W W, Center D M, Holgate S T, Djukanovic R. J Immunol 2000 Jan. 1, 164(1), 412-8; Checkpoints for regulation of development and IFN-γ production by Th1 cells in TCR-transgenic models. Anne O'Garra. Immunology 1999 65, 41-44; Overproduction of Th2-specific chemokines in NC/Nga mice exhibiting atopic dermatitis-like lesions. Christian Vestergaard et al. J Clin Invest 1999 104, 1097-1105; Involvement of nuclear factor-kappa, B activation in IgE synthesis in human B cells. Yanagihara Y, Basaki Y, Ikizawa K, Kajiwara K, Koshio T, Akiyama K. J Allergy Clin Immunol 1996 December 98 (6 Pt 2):S224-9).
It has also been suggested that activation of NF-κB is one of the important mechanisms in psoriasis vulgaris, contact dermatitis, and the like (Macrophage-derived cytokine and nuclear factor kappaB p65 expression in synovial membrane and skin of patients with psoriatic arthritis. Danning C L, Illei G G, Hitchon C, Greer M R, Boumpas D T, McInnes I B Arthritis Rheum 2000 June, 43(6), 1244-56; Activation of nuclear factor-kappa B and gene expression in human endothelial cells by the common haptens nickel and cobalt. Goebeler M, Roth J, Brocker E B, Sorg C, Schulze-Osthoff K. J Immunol 1995 Sep. 1; 155(5):2459-67).
GATA-3 is a transcription factor which plays an important role in the onset and the progression of allergic diseases (Upregulation of the transcription factor GATA-3 in upper airway mucosa after in vivo and in vitro allergen challenge. Nakamura Y, Christodoulopoulos P, Cameron L, Wright E, Lavigne F, Toda M, Muro S, Ray A, Eidelman D H, Minshall E, Hamid Q. J Allergy Clin Immunol 2000 June 105(6Pt1), 1146-52; Inhibition of allergic inflammation in a murine model of asthma by expression of a dominant-negative mutant of GATA-3, Zhang D H, Yang L, Cohn L, Parkyn L, Homer R, Ray P, Ray A, Immunity 1999 October 11(4), 473-82).
STAT-6 is a transcription factor which controls the expression regulation mechanism of IL-4 and reaction of helper T cells by IL-4 (Wang L H, Yang X Y, Kirken R A, Resau J H, Farrar W L. Targeted disruption of stat6 DNA binding activity by an oligonucleotide decoy blocks IL-4-driven T(H)2 cell response. Blood 2000 Feb. 15, 95(4), 1249-57).
AP-1 is a transcription factor which plays an important role in the onset and the progression of allergic diseases (Transcriptional control of the IL-5 gene by human helper T cells: IL-5 synthesis is regulated independently from IL-2 or IL-4 synthesis. Mori A, Kaminuma O, Mikami T, Inoue S, Okumura Y, Akiyama K, Okudaira H. J Allergy Clin Immunol 1999 May 103 (5 Pt2), S429-36; The glucocorticoid receptor gene as a candidate for gene therapy in asthma, Mathieu M, Gougat C, Jaffuel D, Danielsen M, Godard P, Bousquet J, Demoly P, Gene Ther 1999 February, 6(2), 245-52).
Stat-1 and Ets are also transcription factors considered to play an important role in the onset and the progression of allergic diseases.
As described above, transcription factors containing NF-κB have been suggested to be involved in various diseases through expression of various genes under the transcription control thereof, but no method for effective treatment against these diseases has been provided.